Colony stimulating factor 1 (CSF-1) is a secreted cytokine which is a regulator of the production, differentiation, and function of macrophages, monocytes, and other hematopoietic precursor cells. The encoded CSF-1 receptor (CSF-1R) protein is a tyrosine kinase transmembrane receptor and member of the CSF1/PDGF receptor family of tyrosine-protein kinases. Binding of CSF-1 to CSF-1R induces the activation of tyrosine kinase such as PI3K and MEK. The CSF-1 receptor mediates the majority of the biological effects of this cytokine which can include anti-inflammatory activity. CSF-1 receptor inhibition has been theorized to have utility in the treatment of cancer, but was considered unlikely as a therapeutic technique to be effective in the treatment of inflammatory disease (Hume et al. Blood 119:1810-1820 (2012)).
Vascular endothelial growth factor (VEGF) is a known regulator of angiogenesis and neovascularization, and has been shown to be a key mediator of neovascularization associated with tumors and intraocular disorders (Ferrara et al. Endocr. Rev. 18:4-25 (1997)). The concentration of VEGF in eye fluids are highly correlated to the presence of active proliferation of blood vessels in patients with diabetic and other ischemia-related retinopathies (Berkman et al., J Clin Invest 91:153-159 (1993); Brown et al. Human Pathol. 26:86-91 (1995); Brown et al. Cancer Res. 53:4727-4735 (1993); Mattern et al. Brit. J. Cancer. 73:931-934 (1996); and Dvorak et al. Am J. Pathol. 146:1029-1039 (1995); Aiello et al. N. Engl. J. Med. 331:1480-1487 (1994)). In addition, studies have shown the presence of localized VEGF in choroidal neovascular membranes in patients affected by age-related macular degeneration (AMD) (Lopez et al. Invest. Ophtalmo. Vis. Sci. 37:855-868 (1996)). Several anti-VEGF therapeutics have been developed for the treatment of ocular disorders such as AMD and diabetic retinopathy; such therapeutics include ranibizumab (LUCENTIS®) and aflibercept (EYLEA®).